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Biogenesis and function of fibrillin assemblies

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Abstract

Fibrillin-1 and fibrillin-2 are large cysteine-rich glycoproteins that serve two key physiological functions: as supporting structures that impart tissue integrity and as regulators of signaling events that instruct cell performance. The structural role of fibrillins is exerted through the temporal and hierarchical assembly of microfibrils and elastic fibers, whereas the instructive role reflects the ability of fibrillins to sequester transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) complexes in the extracellular matrix. Characterization of fibrillin mutations in human patients and in genetically engineered mice has demonstrated that perturbation of either function manifests in disease. More generally, these studies have indicated that fibrillins are integral components of a broader biological network of extracellular, cell surface, and signaling molecules that orchestrate morphogenetic and homeostatic programs in multiple organ systems. They have also suggested that the relative composition of fibrillin-rich microfibrils imparts contextual specificity to TGFβ and BMP signaling by concentrating the ligands locally so as to regulate cell differentiation within a spatial context during organ formation (positive regulation) and by restricting their bioavailability so as to modulate cell performance in a timely fashion during tissue remodeling/repair (negative regulation). Correlative evidence suggests functional coupling of the cell-directed assembly of microfibrils and targeting of TGFβ and BMP complexes to fibrillins. Hence, the emerging view is that fibrillin-rich microfibrils are molecular integrators of structural and instructive signals, with TGFβ and BMPs as the nodal points that convert extracellular inputs into discrete and context-dependent cellular responses.

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Acknowledgements

We are indebted to Karen Johnson for organizing the manuscript and to Noe Charbonneau for preparing the illustrations.

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Authors and Affiliations

  1. Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, N.Y., USA

    Francesco Ramirez

  2. Department of Biochemistry and Molecular Biology, Shriners Hospital for Children, Oregon Health & Science University, Portland, Ore., USA

    Lynn Y. Sakai

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  1. Francesco Ramirez
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  2. Lynn Y. Sakai
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Correspondence to Francesco Ramirez.

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The described studies from the authors’ laboratories were supported by grants from the National Institutes of Health (AR-049698 and AR-42044) and the Shriners Hospital for Children.

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Ramirez, F., Sakai, L.Y. Biogenesis and function of fibrillin assemblies. Cell Tissue Res 339, 71–82 (2010). https://doi.org/10.1007/s00441-009-0822-x

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  • DOI: https://doi.org/10.1007/s00441-009-0822-x

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